Background Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurobehavioral disorders in which behavioral abnormalities are common but often not recognized. Objective To bring to life the actual descriptions rendered by our patients of their unusual experiences. Methods Members of the Parkinson Study Group were asked to provide illustrative examples of particularly memorable abnormal behaviors that their own PD patients or family members reported. Results These recollections were deidentified and sorted into categories. These disorders include the classically described syndromes of Capgras, Cotard, Diogenes, Ekbom, Othello as well as overlap parasomnias, and impulse control disorders. Conclusion Patients with PD often have had unusual experiences that they may not share without inquiries by their healthcare providers, fearful of how they will be perceived. Sensitive inquiries are required to reveal these problems. We believe that reading about real experiences will help sensitize the reader.

BackgroundAnxiety and other non-motor symptoms can greatly diminish quality of life in people with Parkinson's Disease (PD). Yet, few randomized controlled trials (RCTs) have assessed accessible, non-pharmacological mental health treatments for people with PD.ObjectiveTo assess the feasibility and impact of brief, remotely-delivered meditation and breathwork on neuropsychiatric symptoms in people with PD.MethodsIn this 18-week RCT, intervention participants attended weekly webinars for six weeks, while waitlisted controls maintained their usual routine before crossing over at six weeks. Participants were assessed for weekly compliance trends (primary outcome) and changes in anxiety (primary outcome), depression, perceived stress, and other non-motor symptoms at 6-week intervals: baseline and weeks 6 (T2), 12 (T3), and 18 (T4). Weekly compliance was collected in each group for 12 weeks. Anxiety was measured using the Parkinson's Anxiety Scale.ResultsThere was a significant decrease in the primary outcome, anxiety, in the intervention group (n = 17) compared to the waitlist control (n = 21) after 6 weeks of meditation and breathwork practice (mean difference (MD)= -5.0, 95% CI [-9.5, -0.49], P = .03). Within-group analysis further confirmed a significant reduction in anxiety (MD = -4.7, 95% CI [2.10,7.33], P < .001) in the intervention group (n = 28). Thirty-one percent of participants met the compliance definition.ConclusionRemotely-delivered meditation and breathwork through the BSM program significantly reduced anxiety in individuals with PD in our study and may be a promising non-pharmacological therapy. A larger RCT with continuous wellness coaching is warranted to more rigorously assess efficacy and optimize protocols.Clinical trial registration: ClinicalTrials.gov, NCT05335850, https://clinicaltrials.gov/study/NCT05335850.

Importance:Magnetic resonance imaging (MRI) paired with appropriate disease-specific machine learning holds promise for the clinical differentiation of Parkinson disease (PD), multiple system atrophy (MSA) parkinsonian variant, and progressive supranuclear palsy (PSP). A prospective study is needed to test whether the approach meets primary end points to be considered in a diagnostic workup. Objective:To assess the discriminative performance of Automated Imaging Differentiation for Parkinsonism (AIDP) using 3-T diffusion MRI and support vector machine (SVM) learning. Design, Setting, and Participants:This was a prospective, multicenter cohort study conducted from July 2021 to January 2024 across 21 Parkinson Study Group sites (US/Canada). Included were patients with PD, MSA, and PSP with established criteria and unanimous agreement in the clinical diagnosis among 3 independent, blinded neurologists who specialize in movement disorders. Patients were assigned to a training set or an independent testing set. Exposure:MRI. Main Outcomes and Measures:Area under the receiver operating characteristic curve (AUROC) in the testing set for primary model end points of PD vs atypical parkinsonism, MSA vs PSP, PD vs MSA, and PD vs PSP. AIDP was also paired with antemortem MRI to test against postmortem neuropathology in a subset of autopsy cases. Results:A total of 316 patients were screened and 249 patients (mean [SD] age, 67.8 [7.7] years; 155 male [62.2%]) met inclusion criteria. Of these patients, 99 had PD, 53 had MSA, and 97 had PSP. A retrospective cohort of 396 patients (mean [SD] age, 65.8 [8.9] years; 234 male [59.1%]) was also included. Of these patients, 211 had PD, 98 had MSA, and 87 had PSP. Patients were assigned to the training set (78%; 104 prospective, 396 retrospective) or independent testing set, which included 145 (22%; 60 PD, 27 MSA, 58 PSP) prospective patients (mean age, 67.4 [SD 7.7] years; 95 male [65.5%]). The model was robust in differentiating PD vs atypical parkinsonism (AUROC, 0.96; 95% CI, 0.93-0.99; positive predictive value [PPV], 0.91; negative predictive value [NPV], 0.83), MSA vs PSP (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.98; NPV, 0.81), PD vs MSA (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.97; NPV, 0.97), and PD vs PSP (AUROC, 0.98; 95% CI, 0.96-1.00; PPV, 0.92; NPV, 0.98). AIDP predictions were confirmed neuropathologically in 46 of 49 brains (93.9%). Conclusions and Relevance:This prospective multicenter cohort study of AIDP met its primary end points. Results suggest using AIDP in the diagnostic workup for common parkinsonian syndromes.

Polygenic risk scores (PRS) in Parkinson's disease (PD) are associated with disease risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants to biological pathways or cell types. Here, we investigated 8 biological pathways or regions of open chromatin using pathway-specific PRS: alpha-synuclein pathway, adaptive immunity, innate immunity, lysosomal pathway1, endocytic membrane-trafficking pathway, mitochondrial pathway, microglial open chromatin single nucleotide polymorphisms (SNPs), and monocyte open chromatin SNPs. We analysed 7,402 PD patients across 18 'in-person' PD cohorts, and 6,717 patients from the online Fox Insight study. We did not find any significant associations between the 8 pathway-specific PRSs and 8 clinical outcomes in PD. Though this may be due to a lack of statistical power and limited sample size, it may also suggest that the genetic architecture of sporadic PD risk is different from the genetics of PD progression and clinical outcomes.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.

Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of Science Signaling , Abraham et al. define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.

Background:Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives:To investigate the effects of genetic variants on risk and time to LID. Methods:We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID. Results:We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile=1.27, 95% CI=1.03-1.56, p=0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile=1.38, 95% CI=1.07-1.79, p=0.0128; HRfourth_quartile=1.38, 95% CI=1.06-1.78, p=0.0147). Conclusions:This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.

In 2011, the UK medical research charity Cure Parkinson’s set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson’s disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Inflammation is closely associated with many neurodegenerative disorders. Yet whether inflammation causes or exacerbates neurodegeneration has been challenging to define because the two processes are so closely linked. Here we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons control skin inflammation through release of norepinephrine, which suppresses activation of gamma delta T cells via the β2 adrenergic receptor. Strong inflammatory stimulation in the form of the toll like receptor 7 (TLR7) agonist imiquimod (IMQ) causes progressive gamma delta T cell-mediated, Sarm-1-dependent loss of these immunosuppressive sympathetic axons, a positive feedback loop that removes a physiological brake on T cells, resulting in enhanced inflammation and inflammatory axon damage.

Introduction Globally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life. Methods and analysis ‘D-Kids’ is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother–infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups. Ethics and dissemination This trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences. Trial registration number ACTRN12618001174279.

Objective: To test the impact of a novel retromer stabilizer, guanidine hydrazone (2a), on levels of vacuolar protein sorting 35 (VPS35) and on α-synuclein (αS) clearance pathways in human neuroblastoma SH-SY5Y cells. Background: Reducing αS levels in dopaminergic neurons may have neuroprotective potential in Parkinson's disease (PD). Mutations in the VPS35 gene are a rare cause of familial PD. VPS35 is a key component of the retromer, a heteropentameric complex involved in protein trafficking. VPS35 regulates the trafficking of proteins involved in three αS degradation pathways: macroautophagy (MA), chaperone-mediated autophagy (CMA), and the endosomal-lysosomal system (ELS). Design/Methods: We overexpressed exogenous mutant A53T αS by transient transfection in SH-SY5Y cells, co-treated this group with 2a (or vehicle) at 20 uM for 2, 3, 4 or 5 days, and analyzed levels of αS, VPS35, and αS degradation pathway markers by western blot and ELISA. We then looked at the effect of selective MA blockage for 1-day with bafilomycin A1 (BfA1) at 50 nM on the impact of 2a on αS levels. Results: 2a increased VPS35 protein levels (~75%) and retromer function, with increased levels of the VPS35 cargo Sortilin. This correlated with a reduction of phospho-Ser129 αS (~ 80%), an important pathological form of αS, in the cytosolic and soluble fractions and oligomeric αS in the soluble fraction (~ 50%). Furthermore, we found a 2a-induced increase in CMA and MA markers, highlighting its effect on boosting the main αS clearance pathways. After blocking MA, there was a ~60% reduction of phospho-Ser129 αS in the A53T αS-transfected group treated with 2a. Thus, 2a can decrease aS levels even when MA is blocked, potentially by compensatory upregulation of CMA and ELS. Conclusions: These findings link VPS35 to the regulation of multiple aS degradation pathways, and highlight 2a as a promising candidate for neuroprotection in PD. Disclosure: Dr. Persico has nothing to disclose. Dr. ZHANG has nothing to disclose. Miss Tucci has nothing to disclose. Miss Crawford has nothing to disclose. Dr. Simon has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Bial Biotech. An immediate family member of Dr. Simon has stock in Biogen. The institution of Dr. Simon has received research support from Weston Brain Institute. The institution of Dr. Simon has received research support from NIH. The institution of Dr. Simon has received research support from Neuraly. Dr. Simon has received personal compensation in the range of $5,000-$9,999 for serving as a Steering Committee Member: SPARK clinical study with Biogen. Dr. Simon has received personal compensation in the range of $500-$4,999 for serving as a Steering Committee Member: NILO-PD clinical study with Michael J Fox Foundation. Dr. Eleuteri has nothing to disclose.

BACKGROUND:Healthcare workers (HCWs) are at high risk of experiencing work-related stress, burnout syndrome, and depression, especially during infectious disease outbreaks like COVID-19. Contributing factors include increased workload, lack of personal protective equipment, and inadequate support from the healthcare administration. Longitudinal studies have shown that the mental health status of HCWs has deteriorated over time. Social support and compassion satisfaction (CS) are protective factors that can mitigate adverse mental health effects. The present longitudinal study examined the mental health status of HCWs during the COVID-19 outbreak and aimed to identify potential predictors and protective factors. METHODS:The study comprised 386 healthcare workers in Hungary and was conducted in two waves (T1 and T2) from January 2021 to January 2022. Participants completed an online survey including the Professional Quality of Life Scale, Maslach Burnout Inventory, demographic and work-related background factors. Statistical analyses included descriptive statistics, and a cross-lagged panel model (CLPM). RESULTS:Frontline HCWs had higher levels of secondary traumatic stress (STS) and emotional exhaustion (EE) than non-frontline healthcare workers. Both groups experienced significant increases in these measures between T1 and T2. The CLPM indicated that EE had a significant lagged effect on STS among frontline workers, while STS had a significant lagged effect on EE among non-frontline workers. CS had a significant protective effect on both STS and EE in both groups. CONCLUSIONS:The findings suggest that CS protects EE and STS, particularly among frontline HCWs. The study also showed that different causative relationships exist between these factors among frontline and non-frontline HCWs, which underlines the possible cyclical relationship between the two depending on the circumstances. The results provide insights into the protective role of positive work experiences and the importance of considering the needs of both frontline and non-frontline HCWs in preventive intervention programs.

BACKGROUND Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Metabolic plasticity of neurons ensures their activity continues when glucose is limited. Walsh and Simon discuss new work by Ashrafi and colleagues (https://doi.org/10.1083/jcb.202305048) that finds Sirtuin 3 directs local metabolic adaptation at synapses during sustained glucose deprivation.

Chorea‐acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites.

Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

Parkinson's Disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), leading to motor and non-motor symptoms. While the exact mechanisms remain complex and multifaceted, several molecular pathways have been implicated in PD pathology, including accumulation of misfolded proteins, impaired mitochondrial function, oxidative stress, inflammation, elevated iron levels, etc. Overall, PD's molecular mechanisms involve a complex interplay between genetic, environmental, and cellular factors that disrupt cellular homeostasis, and ultimately lead to the degeneration of dopaminergic neurons. Recently, emerging evidence highlights ferroptosis, an iron-dependent non-apoptotic cell death process, as a pivotal player in the advancement of PD. Notably, oligomeric α-synuclein (α-syn) generates reactive oxygen species (ROS) and lipid peroxides within cellular membranes, potentially triggering ferroptosis. The loss of dopamine, a hallmark of PD, could predispose neurons to ferroptotic vulnerability. This unique form of cell demise unveils fresh insights into PD pathogenesis, necessitating an exploration of the molecular intricacies connecting ferroptosis and PD progression. In this review, the molecular and regulatory mechanisms of ferroptosis and their connection with the pathological processes of PD have been systematically summarized. Furthermore, the features of ferroptosis in PD animal models and clinical trials targeting ferroptosis as a therapeutic approach in PD patients' management are scrutinized.